Bìol. Tvarin, 2019, volume 21, issue 3, pp. 14–20


O. M. Voloshchuk, G. P. Kopylchuk

This email address is being protected from spambots. You need JavaScript enabled to view it.

Chernivtsi national university named by Yurii Fedkovych, Institute of Biology, Chemistry and Bioresources,
2 Kotsyubinskogo str., Chernivtsi 58012, Ukraine

Nutritional demands in proteins depend on the life stage and health status of organisms. Both humans and experimental animals under stress conditions and especially drug processing become to be more sensitive to the protein deficit in the food. In this study, we examined some acetaminophen-induced metabolic effects potentiated by alimentary protein deprivation (APD) in rat liver. In particular, activities of the liver mitochondrial aspartate aminotransferase and malate dehydrogenase in rat liver were studied in conditions of balanced and imbalanced by protein diets of isocaloric content. It has been found that acute acetaminophen-induced hepatitis in comparison to control does not change the activity of mitochondrial malate dehydrogenase causing simultaneous 4-fold reduction in activity of mitochondrial aspartate aminotransferase and 2.5-fold reduction of mitochondrial oxaloacetate content. Interestingly, alimentary protein deprivation enhances the effects of acetaminophen on the described parameters. Finally, in order to confirm these associations between amount of the protein in the rat diet and physiological measures in their liver with toxic injury, principal component analysis (PCA) was performed. Two principal components characterize changes in physiological measures in our study. Principal component 1 explains about 86 % of the variation among whole dataset mainly related to control group and group subjected to acetaminophen treatment with simultaneous APD. It reveals the tight association of scores for AST activity and oxaloacetate level with control group, which might indicate the high efficiency in the oxaloacetate conversion by AST lacked in both groups with hepatitis. Similarly, principal component 1 explaining the variance in MDH activity shows its linkage to the control group, indicating the importance of MDH for the health status of control animals. On the other side, principal component 2 reveals close association between lactate and pyruvate levels as well as cytosolic NAD+/NADH ratio with acetaminophen-treated group of animals subjected to APD, confirming that toxic liver injury associated with low protein consumption leads to increased lactate-pyruvate turnover in cytosol affecting. This potentially might be associated with energy-generating dysfunction in liver under toxic hepatitis on the background of dietary protein deficiency.


  1. Carvalho N. R., da Rosa F., da Silva M. H., Tassi C. C., Dalla Corte C. L., Carbajo-Pescador S., Mauriz J. L., González-Gallego J., Soares F. A. New therapeutic approach: diphenyl diselenide reduces mitochondrial dysfunction in acetaminophen-
    induced acute liver failure. PLoS One, 2013, vol. 8, issue 12, e81961. DOI: 10.1371/journal.pone.0081961.
  2. Cetica P., Pintos L., Dalvit G., Beconi M. Involvement of enzymes of amino acid metabolism and tricarboxylic acid cycle in bovine oocyte maturation in vitro. Reproduction, 2003, vol. 126, issue 6, pp. 753–763. DOI: 10.1530/reprod/126.6.753.
  3. Khyzhnyak S. V., Sorokina L. V., Stepanova L. I., Kaplia A. A. Functional and dynamic state of inner mitochondrial membrane of sarcoma 37 in mice under administration of sodium dichloroacetate. The Ukrainian Biochemical Journal, 2014, vol. 86, issue 6, pp. 106–118. DOI: 10.15407/ubj86.06.106.
  4. Kopylchuk G. P., Voloshchuk O. M. Peculiarities of the free radical processes in rat liver mitochondria under toxic hepatitis on the background of alimentary protein deficiency. The Ukrainian Biochemical Journal, 2016, vol. 88, issue 2, pp. 66–72. DOI: 10.15407/ubj88.02.066.
  5. Lerapetritou M. G., Georgopoulos P. G., Roth C. M., Androulakis L. P. Tissue-level modeling of xenobiotic metabolism in liver: An emerging tool for enabling clinical translational research. Clinical and Translational Science, 2009, vol. 2, issue 3, pp. 228–237. DOI: 10.1111/j.1752-8062.2009.00092.x.
  6. Licata A. Adverse drug reactions and organ damage: The liver. European Journal of Internal Medicine, 2016, vol. 28, pp. 9–16. DOI: 10.1016/j.ejim.20112.017.
  7. Mehrotra R. N., Hasan T. Detection and spectrophotometric determination of pyruvic acid. Analytical Letters, 1986, vol. 19, issue 17–18, pp. 1713–1724. DOI: 10.1080/00032718608066497.
  8. Mund M. E., Quarcoo D., Gyo C., Brüggmann D., Groneberg D. A. Paracetamol as a toxic substance for children: aspects of legislation in selected countries. Journal of Occupational Medicine and Toxicology, 2015, vol. 10, p. 43. DOI: 10.1186/s12995-015-0084-3.
  9. Olayinka E. T., Ore A., Ola O. S., Adeyemo O. A. Protective effect of quercetin on melphalan-induced oxidative stress and impaired renal and hepatic functions in rat. Chemotherapy Research and Practice, 2014, vol. 2014, article ID 936526, 8 p. DOI: 10.1155/2014/936526.
  10. Sangar V., Eddy J. A., Simeonidis E., Price N. D. Mechanistic modeling of aberrant energy metabolism in human disease. Frontiers in Physiology, 2012, vol. 3, article ID 404, 10 p. DOI: 10.3389/fphys.2012.00404.
  11. Schenkman J. B., Cinti D. L. Preparation of microsomes with calcium. Methods in Enzymology, 1978, vol. 52, pp. 83–89. DOI: 10.1016/S0076-6879(78)
  12. Somanawat K., Thong-Ngam D., Klaikeaw N. Curcumin attenuated paracetamol overdose induced hepatitis. World Journal of Gastroenterology, 2013, vol. 19, issue 12, pp. 1962–1967. DOI: 10.3748/wjg.v19.i12.1962.
  13. Sun F., Dai C., Xie J., Hu X. Biochemical issues in estimation of cytosolic free NAD/NADH ratio. PLoS One, 2012, vol. 7, issue 5, e34525. DOI: 10.1371/journal.pone.0034525.
  14. Voloshchuk O. M., Kopylchuk G. P. Activity of liver mitochondrial NAD+-dependent dehydrogenases of the Krebs cycle in rats with acetaminophen-induced hepatitis developed under conditions of alimentary protein deficiency. Biomeditsinskaya Khimiya, 2016, vol. 62, issue 2, pp. 169–172. DOI: 10.18097/PBMC20166202169. (in Russian)
  15. Wang C., Chen H., Zhang J., Hong Y., Ding X., Ying W. Malate-aspartate shuttle mediates the intracellular ATP levels, antioxidation capacity and survival of differentiated PC12 cells. International Journal of Physiology, Pathophysiology and Pharmacology, 2014, vol. 6, issue 2, pp. 109–114.
  16. Williamson D. H., Lund P., Krebs H. A. The redox state of free nicotinamide-adenine dinucleotide in the cytoplasm and mitochondria of rat liver. Biochemical Journal, 1967, vol. 103, issue 2, pp. 514–527. DOI: 10.1042/bj1030514.
  17. Wu G. Dietary protein intake and human health. Food & Function, 2016, vol. 7, issue 3, pp. 1251–1265. DOI: 10.1039/C5FO01530H.
  18. Ying W. NAD+/NADH and NADP+/NADPH in cellular functions and cell death: regulation and biological consequences. Antioxidants & Redox Signaling, 2008, vol. 10, issue 2, pp. 179–206. DOI: 10.1089/ars.2007.1672.
  19. Zhou Y.-H., Shi D., Yuan B., Sun Q.-J, Jiao B.-H., Sun J. J., Miao M.-Y. Mitochondrial ultrastructure & release of proteins during liver regeneration. The Indian Journal of Medical Research, 2008, vol. 128, issue 2, pp. 157–164.

Download full text in PDF